Researchers find the roots of leukemia relapse are present at diagnosis, uncovering clues to new treatment approaches

Despite
significant advances in the treatment of acute lymphoblastic leukemia (ALL),
the disease often returns aggressively in many patients after treatment. It is
thought that current chemotherapies eliminate most leukemia cells, but groups
of resistant cells may survive therapy, progress and eventually cause relapse.
Dr. John Dick and collaborators have found these cells.

In a recent study published in Cancer Discovery, Dick and collaborators were able to identify and isolate groups of genetically distinct cells that drive ALL relapse.

The cells, termed
diagnosis relapse initiating (dRI) clones were found to have genetic
characteristics that differ from the other leukemia cells that are eliminated
by treatment.

The study, along with a complementary study published in Blood Cancer Discovery, unraveled the genetic, epigenetic, metabolic and pro-survival molecular pathways driving treatment resistance. Together, these papers provide an integrated genomic and functional approach to describing the underlying genetics and mechanisms of relapse for ALL.

Interestingly,
the research group discovered that dRI clones are present at diagnosis, opening
opportunities to improve treatment up-front, devise drugs that target these
resistant cells and prevent relapse from ever occurring.

Dr. Stephanie Dobson

“Our study has shown that genetic clones that contribute to disease recurrence already possess characteristics such as therapeutic tolerance that distinguish them from other clones at diagnosis,” says Dr. Stephanie Dobson, first author of the study who performed this research as a member of John Dick’s Lab. “Being able to isolate these clones at diagnosis, sometimes years prior to disease recurrence, has enabled us to begin to profile the properties allowing these particular cells to survive and act as reservoirs for relapse. This knowledge can be used to enhance our therapeutic approaches for targeting relapse and relapse-fated cells.”

“Xenografting
added considerable new insight into the evolutionary fates and patterns of
subclones obtained from diagnosis samples,” says John Dick, who is the
co-senior author of the study, Senior Scientist at the Princess Margaret Cancer
Centre and leader of OICR’s Acute Leukemia Translational Research Initiative.
“We were able to gather extensive information about the genetics of the
subclones from our models, which helped us describe the trajectories of each
subclone and the order in which they acquired mutations.”

Ordering
these mutations relied on the advanced machine learning algorithms designed by
Dr. Quaid Morris and Jeff Wintersinger at the University of Toronto.

Research
efforts are underway to build on these discoveries and determine how to block
dRI clones.

The
study was led by researchers at St. Jude Children’s Research Hospital, the
Princess Margaret Cancer Centre and the University of Toronto and supported in
part by OICR’s Acute Leukemia Translational Research Initiative.

Researchers identify five subtypes of pancreatic cancer,
uncovering new opportunities for targeted treatment of the aggressive disease

Toronto – (January 13, 2020) Researchers at the
Ontario Institute for Cancer Research (OICR) and the University Health Network
(UHN) have discovered detailed new information about the subtypes of pancreatic
cancer. A better understanding of the disease groups may lead to new treatment
options and improved clinical outcomes for this lethal disease.

The
study, published today in Nature Genetics,
represents the most comprehensive analysis of the molecular subtypes of
pancreatic cancer to date. Through detailed genomic and transcriptomic
analyses, the research group identified five distinct subtypes of the disease
(Basal-like-A, Basal-like-B, Classical-A, Classical-B, and Hybrid) with unique
molecular properties that could be targeted with novel chemotherapies,
biologics and immunotherapies.

“Therapy development for pancreatic cancer has been hindered by an incomplete knowledge of the molecular subtypes of this deadly disease,” says lead author Dr. Faiyaz Notta, Co-Leader of OICR’s Pancreatic Cancer Translational Research Initiative (PanCuRx) and Scientist at UHN’s Princess Margaret Cancer Centre. “By rigorously analyzing advanced pancreatic cancers – which is the stage of disease that most patients have when they’re diagnosed – we were able to create a framework. This will help us develop better predictive models of disease progression that can assist in personalizing treatment decisions and lead to new targeted therapies.”

The
study is based on data from more than 300 patients with both early stage and advanced
pancreatic cancer who participated in COMPASS, a first-of-its-kind clinical
trial that is breaking new ground in discovery science and personalized
pancreatic cancer treatment. COMPASS is enabled by advanced pathology
laboratory techniques at UHN and OICR, and next generation sequencing at OICR.

“Most
pancreatic cancer research is focused solely on early stage – or resectable –
tumours, but in reality, pancreatic cancer is often found in patients after it
has advanced and spread to other organs,” says Notta. “COMPASS allowed us to
look into these advanced cancers while treating these patients, develop a
better understanding of the biology behind metastatic pancreatic cancer, and shed
light on the mechanisms driving disease progression.”

Interestingly,
the Basal-like-A subtype, which had been difficult to observe before this study,
was linked with a specific genetic abnormality. Most of the Basal-like-A
tumours harboured several copies of a mutated KRAS gene, also known as a genetic amplification of mutant KRAS. The research group hypothesizes
that some of the subtypes arise from specific genetic changes that occur as pancreatic
cancer develops.

“This
research opens new doors for therapeutic development,” says
Dr. Steven Gallinger, Co-Leader of OICR’s PanCuRx, Surgical Oncologist at UHN
and Senior Investigator, Lunenfeld Tanenbaum Research Institute at Mount Sinai
Hospital. “We look forward to capitalizing on the promise of these discoveries,
building on our understanding of pancreatic cancer subtypes, and bringing new
treatments to patients with the disease.”

This research was supported by OICR through funding provided by the Government of Ontario, and by the Wallace McCain Centre for Pancreatic Cancer by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, the Canadian Cancer Society Research Institute, the Pancreatic Cancer Canada Foundation, the Canadian Friends of the Hebrew University and the Cancer Research Society (no. 23383).

For Dr. Osvaldo Espin-Garcia, an industry-based
job wouldn’t suffice. Having already worked in banking, insurance and
telecommunications, Espin-Garcia found that his skills in statistics could be
applied to a field that he was much more passionate about. For him, that was
health research.

Combining his skills in math with his interest
in health, Espin-Garcia left his job in Mexico and moved to Canada to pursue
the University of Waterloo’s Master of Mathematics program. His strong academic
performance secured him an internship at the Princess Margaret Cancer Centre
(PM) where he found his niche in statistical genetics.

“Despite advancements in sequencing
technologies, the path between a new -omics discovery and applying that
discovery in the clinic remains cumbersome and often costly, especially in
large-scale studies,” says Espin-Garcia, who recently completed his PhD at the
University of Toronto’s Dalla Lana School of Public Health. “We can use
statistical techniques and tools to design better trials and make sense of this
sequencing data in more efficient ways.”

Espin-Garcia’s
internship laid the foundations for his PhD research, where he developed
statistical methods and analysis tools to examine the data from genome-wide
studies – studies that look at the entire set of genes across many individuals.

In these studies, researchers often examine a
sample subset of patient genomes from a large group of patients. These samples
are often selected randomly, but Espin-Garcia’s methods allow researchers to
select these patients in a “smarter” way.

“Choosing patients randomly is an inefficient way
to perform post-genome-wide studies since this strategy fails to incorporate the
information that is already available,” says Espin-Garcia. “Our methods allow
us to select subgroups of patients whose data will give us rich insights into
challenging research questions. That’s what I’m here for, I’m here to help
address important and challenging questions in health.”

For this work, Espin-Garcia was awarded a Biostatistics Training Initiative
(BTI) Fellowship, which helped him fast-track the development of his methods
and the completion of his PhD.

Now, as a Senior Biostatistician at PM, he is
specializing in gastrointestinal cancer studies and continues to develop and
apply new tools to support the clinical cancer research community.

“I am grateful for the support I’ve received
throughout my training to build my collaborative relationships with clinicians
and scientists and learn from incredible mentors,” says Espin-Garcia. “I look
forward to supporting more cutting-edge clinical cancer research in the
future.”

BTI, a training program co-led by OICR, the
University of Waterloo and McMaster University, has supported numerous fellows,
like Espin-Garcia, and other studentships over the last decade.

Collaborative research group maps the three-dimensional genomic
structure of glioblastoma and discovers a new therapeutic strategy to eliminate
cells at the roots of these brain tumours

Current treatment for glioblastoma – the most common type of malignant brain cancer in adults – is often palliative, but new research approaches have pointed to new promising therapeutic strategies.

A collaborative study, recently published in Genome
Research, has mapped the three-dimensional configuration
of the genome in glioblastoma and discovered a new way to target glioblastoma
stem cells – the self-renewing cells that are thought to be the root cause of
tumour recurrence.

The research group integrated three-dimensional genome maps
of glioblastoma with other chromatin and transcriptional datasets to describe the
mechanisms regulating gene expression and detail the mechanisms that are
specific to glioblastoma stem cells. They are one of the first groups in the
world to perform three-dimensional genomic analyses in patient-derived tumour samples.

Dr. Mathieu Lupien

“The 3D configuration of the genome has garnered much attention over the last decade as a complex, dynamic and crucial feature of gene regulation,” says Dr. Mathieu Lupien, Senior Scientist at the Princess Margaret Cancer Centre, OICR Investigator and co-author of the study. “Looking at how the genome is folded and sets contacts between regions tens to thousands of kilobases apart allowed us to find a new way to potentially tackle glioblastoma.”

Through their study, the group discovered that CD276 – a
gene which is normally involved with repressing immune responses – has a very
important role in maintaining stem-cell-like properties in glioblastoma stem
cells. Further, they showed that targeting CD276 may be an effective new
strategy to kill cancer stem cells in these tumours.

“This research was fueled by an impressive community of
scientists in the area who are committed to finding new solutions for patients
with brain cancer,” Lupien says. “Our findings have emphasized the significance
of three-dimensional architectures in genomic studies and the need to further develop
related methodologies to make sense of this intricacies.”

Senior author of the study, Dr. Marco Gallo will continue
to investigate CD276 as a potential therapeutic target for glioblastoma. He
plans to further delineate the architecture of these cancer stem cells to
identify more new strategies to tackle brain tumours.

Dr. Marco Gallo

“A key problem with current glioblastoma treatments is that they mostly kill proliferating cells, whereas we know that glioblastoma stem cells are slow-cycling, or dormant. Markers like CD276 can potentially be targeted with immunotherapy approaches, which could be an effective way of killing cancer stem cells, irrespective of how slowly they proliferate,” says Gallo, who is an Assistant Professor at the University of Calgary. “Being able to kill cancer stem cells in glioblastoma could have strong implications for our ability to prevent relapses.”

Read
more about OICR’s Brain Cancer Translational Research Initiative on oicr.on.ca
or read about the Initiative’s current findings on OICR
News.

The Lebovic Fellowship program connects scientists in Israel and Ontario, leading to the validation of a new drug candidate for leukemia and the optimization of a new potential cancer vaccine

Three years ago, the Institute
for Medical Research Israel-Canada (IMRIC) received a donation from Joseph and Wolf Lebovic – two
brothers who are Holocaust survivors, Canadian immigrants, avid philanthropists
and recently-appointed Members of the Order of Canada. Their vision was to
strengthen collaboration between the outstanding researchers in Israel and
those in Ontario to accelerate cancer research.

They created the Joseph
and Wolf Lebovic Fellowship Program, which paired together laboratories
specializing in complementary subjects. The Program’s first round of projects
officially came to a successful close today and here we recognize the progress
made thanks to the generous donation of the Lebovic brothers.

Ben-Neriah’s lab in Israel had
developed a new compound and showed it may be a valuable anti-leukemia drug,
but they couldn’t explain why the drug was only effective in animal models that
had strong immune systems. Understanding the relationship between the drug and
the immune system would allow them to validate which leukemia subtypes would
respond to their therapeutic approach.

John Dick’s lab had developed
the gold standard for evaluating the efficacy of leukemia drugs in animal
models using sophisticated patient-derived xenograft mouse models. Through this
fellowship, the Ben-Neriah Lab teamed up with the Dick lab to learn from their
expertise and gain insights into their experimental models.

Collaborative research group performs the most comprehensive analysis of curable prostate cancer to date, finds key connections between different data types

As cancer researchers delve deeper into different omics studies, and technologies enable
their ability to do so, it is becoming increasingly important to understand how
these areas of research are interconnected. Previous studies across multiple omes – such as the genome, proteome,
transcriptome or epigenome – have led to important discoveries in colorectal
cancer and ovarian cancer, but prostate cancer remains largely unresolved.
Researchers from the Canadian Prostate Cancer Genome Network (CPC-GENE) set out
to unravel some of these mysteries.

In the most recent CPC-GENE study, published today in Cancer
Cell, the research group
integrated multiple levels of omics analyses to better understand the biology
of intermediate-risk prostate cancer – a type of cancer in which it is
notoriously difficult to predict and treat accordingly. A better understanding
of this disease could lead to improved tests that can determine which tumours
are aggressive and require aggressive treatment, while helping spare those
whose cancer will never become aggressive the negative side effects of
treatment.

“We cannot overlook the important information that we gain from
looking at the bigger picture,” says Julie Livingstone, bioinformatician at
OICR and co-author of the study. “In this case, this means looking at prostate
cancer from multiple angles – or multiple omes
– to potentially find new markers of aggressive disease.”

The study explored 76 prostate cancer tumours and found new
combinations of information that could act as a better predictor of a patient’s
chance of relapse than any single piece of information alone. More
specifically, they identified that the combination of protein and methylation
data could, on average, predict the severity of a tumour better than looking at
just the proteins – the proteome – or just the methylation patterns – the methylome
– alone.

“Integrating datatypes is anything but straightforward, but
it illuminates interesting aspects about prostate cancer that we haven’t seen
before,” says Livingstone. “In the future, we intend to pursue our
multi-omic investigation and translate
this understanding into better tools to inform treatment selection for men with
this disease.”

OICR offers new CT calibration service as part of its Collaborative Research Resources portfolio

Using imaging devices to help make treatment decisions in the clinic requires rigorous testing, quality assurance and routine calibration of the imaging machinery. These standards are especially important when the imaging technology is novel or unique, such as in the case of perfusion imaging – a relatively new technique used to diagnose a cancer’s stage by showing how blood flows through the tumour.

Ten new projects were selected in the pipeline’s inaugural funding round, highlighting Ontario’s strengths in collaboration and drug discovery.

Toronto (December 4, 2017) – The Ontario Institute for Cancer Research (OICR) today announced the Cancer Therapeutics Innovation Pipeline (CTIP) initiative and the first 10 projects selected in CTIP’s inaugural round of funding. CTIP aims to support the local translation of Ontario discoveries into therapies with the potential for improving the lives of cancer patients. The funding will create a new pipeline of promising drugs in development, and attract the partnerships and investment to the province necessary for further clinical development and testing.

“Ontario congratulates OICR on this innovative approach to driving the development of new cancer therapies,” says Reza Moridi, Ontario’s Minister of Research, Innovation and Science. “The Cancer Therapeutics Innovation Pipeline will help ensure that promising discoveries get the support they need to move from lab bench to commercialization, and get to patients faster.”

Toronto (September 6, 2017) – Understanding a cancer’s genetics is key to selecting targeted therapies that are likely to be of the most benefit to a patient. The Ontario Institute for Cancer Research (OICR) today announced a new study, called Ontario-wide Cancer TArgeted Nucleic Acid Evaluation (OCTANE). OCTANE will use next-generation genome sequencing technology to bring a unified molecular profiling approach to five Ontario cancer centres.

Prostate cancer researchers have mapped the impact of an acquired mutation that alters epigenetic identity, the make-up of DNA, in about 50 per cent of patient tumour samples. The discovery also identifies a new opportunity for targeted therapy.

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